Effects and mechanism of the bile acid (farnesoid X) receptor on the Wnt/β‑catenin signaling pathway in colon cancer

Mao,Jiayu; Chen,Xueqi; Wang,Chunsaier; Li,Wenbin; Li,Jingnan

doi:10.3892/ol.2020.11545

Effects and mechanism of the bile acid (farnesoid X) receptor on the Wnt/β‑catenin signaling pathway in colon cancer

Authors:
- Jiayu Mao
- Xueqi Chen
- Chunsaier Wang
- Wenbin Li
- Jingnan Li
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Affiliations: Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing 100730, P.R. China
Published online on: April 16, 2020 https://doi.org/10.3892/ol.2020.11545
Pages: 337-345
Copyright: © Mao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The downregulation of farnesoid X receptor (FXR; gene name, nuclear receptor subfamily 1 group h member 4), an enteric nuclear bile acid receptor, has been reported in colorectal carcinoma (CRC), and FXR expression has been inversely correlated with CRC stage and clinical outcome. FXR knockdown in chronic colitis mouse models of intestinal tumorigenesis results in early mortality and increased tumor progression via promoting Wnt signaling. The aim of the present study was to explore the effects and mechanism of FXR on the Wnt/β‑catenin signal pathway in CRC. FXR and β‑catenin protein expression levels were detected in an ulcerative colitis mouse model and human colon cancer cell lines (HT‑29, Caco‑2 and HCT‑116). Gain‑ and loss‑of‑function studies were conducted by transfecting colon cancer cells with FXR siRNA and treating them with the FXR agonist GW4064. Subsequently, β‑catenin transcriptional activity was measured using the dual‑luciferase assay, and β‑catenin/TCF4 complex levels and β‑catenin protein and mRNA expression levels were determined. FXR and β‑catenin expression levels were inversely associated in both the animal model and colon cancer cells. The Wnt signaling pathway was activated by increased β‑catenin/TCF4 complex levels upon FXR silencing; however, mRNA and protein levels of β‑catenin were not significantly affected. The FXR agonist GW4064 significantly inhibited the proliferation of cells but promoted the transcriptional activity of β‑catenin. Thus, the present study demonstrated that FXR influences the Wnt/β‑catenin signaling pathway. Furthermore, loss of FXR expression promotes the transcriptional activity of β‑catenin, whereas FXR activation results in the opposite effect.

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1	Reddy BS: Diet and excretion of bile acids. Cancer Res. 41:3766–3768. 1981.PubMed/NCBI
2	Lagergren J, Ye W and Ekbom A: Intestinal cancer after cholecystectomy: Is bile involved in carcinogenesis? Gastroenterology. 121:542–547. 2001. View Article : Google Scholar : PubMed/NCBI
3	Peterlik M: Role of bile acid secretion in human colorectal cancer. Wien Med Wochenschr. 158:539–541. 2008. View Article : Google Scholar : PubMed/NCBI
4	Pearson JR, Gill CI and Rowland IR: Diet, fecal water, and colon cancer-development of a biomarker. Nutr Rev. 67:509–526. 2009. View Article : Google Scholar : PubMed/NCBI
5	Kundu S, Kumar S and Bajaj A: Cross-talk between bile acids and gastrointestinal tract for progression and development of cancer and its therapeutic implications. IUBMB Life. 67:514–523. 2015. View Article : Google Scholar : PubMed/NCBI
6	Degirolamo C, Modica S, Palasciano G and Moschetta A: Bile acids and colon cancer: Solving the puzzle with nuclear receptors. Trends Mol Med. 17:564–572. 2011. View Article : Google Scholar : PubMed/NCBI
7	Modica S, Gofflot F, Murzilli S, D'Orazio A, Salvatore L, Pellegrini F, Nicolucci A, Tognoni G, Copetti M, Valanzano R, et al: The intestinal nuclear receptor signature with epithelial localization patterns and expression modulation in tumors. Gastroenterology. 138:636–648, 648.e1-12. 2010. View Article : Google Scholar : PubMed/NCBI
8	Bailey AM, Zhan L, Maru D, Shureiqi I, Pickering CR, Kiriakova G, Izzo J, He N, Wei C, Baladandayuthapani V, et al: FXR silencing in human colon cancer by DNA methylation and KRAS signaling. Am J Physiol Gastrointest Liver Physiol. 306:G48–G58. 2014. View Article : Google Scholar : PubMed/NCBI
9	Lax S, Schauer G, Prein K, Kapitan M, Silbert D, Berghold A, Berger A and Trauner M: Expression of the nuclear bile acid receptor/farnesoid X receptor is reduced in human colon carcinoma compared to nonneoplastic mucosa independent from site and may be associated with adverse prognosis. Int J Cancer. 130:2232–2239. 2012. View Article : Google Scholar : PubMed/NCBI
10	Frankenberg T, Rao A, Chen F, Haywood J, Shneider BL and Dawson PA: Regulation of the mouse organic solute transporter alpha-beta, Ostalpha-Ostbeta, by bile acids. Am J Physiol Gastrointest Liver Physiol. 290:G912–G922. 2006. View Article : Google Scholar : PubMed/NCBI
11	De Gottardi A, Touri F, Maurer CA, Perez A, Maurhofer O, Ventre G, Bentzen CL, Niesor EJ and Dufour JF: The bile acid nuclear receptor FXR and the bile acid binding protein IBABP are differently expressed in colon cancer. Dig Dis Sci. 49:982–989. 2004. View Article : Google Scholar : PubMed/NCBI
12	Gadaleta RM, van Erpecum KJ, Oldenburg B, Willemsen EC, Renooij W, Murzilli S, Klomp LW, Siersema PD, Schipper ME, Danese S, et al: Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease. Gut. 60:463–472. 2011. View Article : Google Scholar : PubMed/NCBI
13	Modica S, Murzilli S, Salvatore L, Schmidt DR and Moschetta A: Nuclear bile acid receptor FXR protects against intestinal tumorigenesis. Cancer Res. 68:9589–9594. 2008. View Article : Google Scholar : PubMed/NCBI
14	Gadaleta RM, Garcia-Irigoyen O and Moschetta A: Bile acids and colon cancer: Is FXR the solution of the conundrum? Mol Aspects Med. 56:66–74. 2017. View Article : Google Scholar : PubMed/NCBI
15	Korinek V, Barker N, Morin PJ, van Wichen D, de Weger R, Kinzler KW, Vogelstein B and Clevers H: Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC-/-colon carcinoma. Science. 275:1784–1787. 1997. View Article : Google Scholar : PubMed/NCBI
16	Mizushima T, Nakagawa H, Kamberov YG, Wilder EL, Klein PS and Rustgi AK: Wnt-1 but not epidermal growth factor induces beta-catenin/T-cell factor-dependent transcription in esophageal cancer cells. Cancer Res. 62:277–282. 2002.PubMed/NCBI
17	Ni D, Liu J, Hu Y, Liu Y, Gu Y, Zhou Q and Xie Y: A1CF-Axin2 signal axis regulates apoptosis and migration in Wilms tumor-derived cells through Wnt/β-catenin pathway. Vitro Cell Dev Biol Anim. 55:252–259. 2019. View Article : Google Scholar
18	Xin Y, He L, Luan Z, Lv H, Yang H, Zhou Y, Zhao X, Zhou W, Yu S, Tan B, et al: E-cadherin mediates the preventive effect of Vitamin D3 in Colitis-associated Carcinogenesis. Inflamm Bowel Dis. 23:1535–1543. 2017. View Article : Google Scholar : PubMed/NCBI
19	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
20	Liu X, Zhang X, Ji L, Gu J, Zhou M and Chen S: Farnesoid X receptor associates with β-catenin and inhibits its activity in hepatocellular carcinoma. Oncotarget. 6:4226–4238. 2015.PubMed/NCBI
21	Peng Z, Raufman JP and Xie G: Src-mediated cross-talk between farnesoid X and epidermal growth factor receptors inhibits human intestinal cell proliferation and tumorigenesis. PLoS One. 7:e484612012. View Article : Google Scholar : PubMed/NCBI
22	Tanaka T, Kohno H, Suzuki R, Yamada Y, Sugie S and Mori H: A novel inflammation-related mouse colon carcinogenesis model induced by azoxymethane and dextran sodium sulfate. Cancer Sci. 94:965–973. 2003. View Article : Google Scholar : PubMed/NCBI
23	Cavard C, Colnot S, Audard V, Benhamouche S, Finzi L, Torre C, Grimber G, Godard C, Terris B and Perret C: Wnt/beta-catenin pathway in hepatocellular carcinoma pathogenesis and liver physiology. Future Oncol. 4:647–660. 2008. View Article : Google Scholar : PubMed/NCBI
24	Cancer Genome Atlas Network, . Comprehensive molecular characterization of human colon and rectal cancer. Nature. 487:330–337. 2012. View Article : Google Scholar : PubMed/NCBI
25	Fu T, Coulter S, Yoshihara E, Oh TG, Fang S, Cayabyab F, Zhu Q, Zhang T, Leblanc M, Liu S, et al: FXR regulates intestinal cancer stem cell proliferation. Cell. 176:1098–1112.e18. 2019. View Article : Google Scholar : PubMed/NCBI
26	Thompson MD, Moghe A, Cornuet P, Marino R, Tian J, Wang P, Ma X, Abrams M, Locker J, Monga SP and Nejak-Bowen K: β-Catenin regulation of farnesoid X receptor signaling and bile acid metabolism during murine cholestasis. Hepatology. 67:955–971. 2018. View Article : Google Scholar : PubMed/NCBI
27	Zhang R, Nakao T, Luo J, Xue Y, Cornuet P, Oertel M, Kosar K, Singh S and Nejak-Bowen K: Activation of WNT/Beta-catenin signaling and regulation of the Farnesoid X Receptor/Beta-catenin complex after murine bile duct ligation. Hepatol Communications. 3:1642–1655. 2019. View Article : Google Scholar
28	Maran RR, Thomas A, Roth M, Sheng Z, Esterly N, Pinson D, Gao X, Zhang Y, Ganapathy V, Gonzalez FJ and Guo GL: Farnesoid X receptor deficiency in mice leads to increased intestinal epithelial cell proliferation and tumor development. J Pharmacol Exp Ther. 328:469–477. 2009. View Article : Google Scholar : PubMed/NCBI
29	Sawa M, Masuda M and Yamada T: Targeting the Wnt signaling pathway in colorectal cancer. Expert Opin Ther Targets. 20:419–429. 2016. View Article : Google Scholar : PubMed/NCBI
30	Mulholland DJ, Dedhar S, Coetzee GA and Nelson CC: Interaction of nuclear receptors with the Wnt/β-catenin/Tcf signaling axis: Wnt you like to know? Endocr Rev. 26:898–915. 2006. View Article : Google Scholar
31	Xiao JH, Ghosn C, Hinchman C, Forbes C, Wang J, Snider N, Cordrey A, Zhao Y and Chandraratna RA: Adenomatous polyposis coli (APC)-independent regulation of beta-catenin degradation via a retinoid X receptor-mediated pathway. J Biol Chem. 278:29954–29962. 2003. View Article : Google Scholar : PubMed/NCBI
32	Han A, Tong C, Hu D, Bi X and Yang W: A direct protein-protein interaction is involved in the suppression of beta-catenin transcription by retinoid X receptor alpha in colorectal cancer cells. Cancer Biol Ther. 7:454–459. 2008. View Article : Google Scholar : PubMed/NCBI
33	Palmer HG, González-Sancho JM, Espada J, Berciano MT, Puig I, Baulida J, Quintanilla M, Cano A, de Herreros AG, Lafarga M and Muñoz A: Vitamin D(3) promotes the differentiation of colon carcinoma cells by the induction of E-cadherin and the inhibition of beta-catenin signaling. J Cell Biol. 154:369–387. 2001. View Article : Google Scholar : PubMed/NCBI